These studies compliment and extend investigations performed in this laboratory to evaluate the hormonal mechanisms controlling development of neonatal glucose homeostasis. Developmentally, the neonate is in a transitional state of glucose homeostasis. While the fetus is completely dependent on his/her mother for glucose delivery, the adult has control of glucose homeostasis since glucose concentration is regulated precisely. In contrast, regulation of glucose may be a major problem even in the term neonate. The neonate must maintain a balance between glucose lack and excess. The dependence of the conceptus on the maternal organism for continuous substrate delivery contrasts with intermittent oral intake by the neonate. Homeostasis should result from an improving balance between developing hormonal systems (insulin and contra-insulin effects, sympathomimetics and neural). These interrelated studies, continuing nineteen years of neonatal carbohydrate kinetic research, will utilize established techniques of our laboratory, available in only a few neonatal laboratories nationally and internationally. We will study kinetics in the term lamb using radioactive isotopes and in the preterm and term human neonate using stable isotopes to answer hypotheses about hormonal control. The first series of studies evaluate the effects of various counter regulatory hormones individually on the suppressed splanchnic (primary hepatic) response to insulin. These studies will use a hypoglycemic hyperinsulinemia model in the neonatal lamb. A second series in the neonatal lamb combines the euglycemic hyperinsulinemic clamp technique with tracer kinetics to evaluate the differential sensitivity of insulin for glucose production versus glucose utilization. Also, we will use sequential doses of galanin, a post ganglionic neurotransmitter, which selectively inhibits insulin secretion to evaluate differential sensitivity to decrements in insulin availability. A third series, studying the human neonate, evaluates regulation of glucose production in response to glucose delivery. These coordinated studies are designed to definitively evaluate the ontogeny of hormonal regulation of neonatal glucose homeostasis. They are critical to our understanding of the physiologic basis of nutritional support neonates require.